Hemodynamic and cardiac effects of spiraprilat in normal and sodium depleted conscious dogs.
The cardiac and hemodynamic effects of 3 doses (0.1, 0.3 and 1 mg/kg, iv) of spiraprilat, the diacid active metabolite of the new angiotensin I converting enzyme inhibitor spirapril, have been investigated and compared to those of saline in chronically implanted conscious dogs at rest. Under a normal sodium diet, spiraprilat, 1 mg/kg, induced significant (at least P less than 0.05) decreases in mean arterial pressure (MAP, -11%), total peripheral resistance (TPR, -21%), left ventricular end diastolic pressure (LVEDP, -15%) and increases in heart rate (HR, +12%) and cardiac output (CO, +16%) whereas dP/dtmax remained unchanged. Spiraprilat-induced tachycardia was not modified by propranolol pre-treatment but was abolished by previous administration of the propranolol-N-methylatropine combination. Spiraprilat, 0.1 mg/kg, did not affect any parameter, but spiraprilat, 0.3 mg/kg, showed intermediate effects. Finally, sodium depletion strongly potentiated spiraprilat effects on MAP, TPR, LVEDP, HR and CO. We conclude that: a), in conscious dogs under normal sodium diet, spiraprilat reduces TPR and MAP through peripheral vasodilating properties; b), spiraprilat-induced tachycardia is mainly related to parasympathetic tone withdrawal, possibly in relation with high and low pressure baroreceptors deactivation; and c), sodium depletion considerably potentiates spiraprilat cardiac and hemodynamic effects.
Gérard
J L
JL
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Pussard
E
E
Berdeaux
A
A
Giudicelli
J F
JF
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004656:Enalapril / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D012964:Sodium / Q000172:deficiency*; D012965:Sodium Chloride / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D012965:Sodium Chloride; D004656:Enalapril; C052555:spirapril; D012964:Sodium